The overall objectives of this proposal are to develop novel approaches to the treatment of human malignancies, to implement early clinical trials of these approaches and to explore in the laboratory potential mechanisms of antitumor effect and resistance, Based on extensive experience, strong preclinical evidence and a clear clinical rationale we believe that the addition of cytokines to a standard regimen of cytotoxic chemotherapy will substantially increase therapeutic effectiveness. This hypothesis will be tested in the present project. Two focused and highly interrelated programs are proposed: 1) The Clinical Trials Program, with the objective of implementing two sequential trials; Phase I study of IL-1 combined with high dose Cisplatinum in patients with metastatic melanoma and a Phase 1 study of IL-1 combined with VP-16 in patients with refractory malignancies. The specific aims of the program are to determine the Maximally Tolerated Dose of the combination of IL-1 and chemotherapy and to evaluate if possible the clinical response rates of combination of treatment. 2) The Laboratory Program, with the objective of measuring the biologic correlates proposed for patients on study and helping to elucidate the mechanisms Involved in therapeutic enhancement. The specific aims are to measure drug pharmacokinetics, platinum-DNA adducts, Glutathione and Metallothionine levels in tumor cells of patients receiving treatment with Cisplatinum and IL-1. In addition to measuring DNA strand breaks and Topoisomerase levels in tumor cells of patients treated with IL-1 and VP-16. All patients treated will have evaluation of peripheral blood hematopoietic progenitor cells as well as induction of cytokines TNF and IL-6. The Laboratory Program will consist of three subunits: Oncopharmacology Laboratory, Cytokine Laboratory and the Tumor Biology and the Hematopoiesis Laboratory. A dedicated group of investigators with a proven track record in studies using cytokines in laboratory research, preclinical experiments, and clinical trials will collaborate on this proposal. We anticipate completion of work in 4 years from the time of award.